Natural killer (NK) cells constitute about 10% of peripheral blood lymphocytes. They kill virus-infected cells and tumor cells through engagement of an array of germ-line encoded activation receptors. In addition to their innate ability to eliminate transformed and infected cells, NK cells perform antibody-dependent cellular cytotoxicity (ADCC) through the low affinity IgG receptor FcgammaRIIIa (also known as CD16), thereby killing IgG-coated target cells and secreting pro-inflammatory cytokines such as IFN-gamma. Plasmodium falciparum, the causative agent of malaria, expresses proteins that are displayed at the surface of infected RBC and promote sequestration of P. falciparum-infected RBC through adhesion to vascular endothelial cells. One of the main objectives in malaria research is to define the mechanisms by which naturally acquired antibodies provide protection. Neutralizing antibodies that prevent P. falciparum merozoite invasion of RBC have been described. However, as merozoites released from late-stage infected RBC rapidly invade uninfected RBC, high antibody titers are needed for inhibition. Antibodies bound to infected RBC promote phagocytosis by myeloid cells, and antibodies bound to merozoites activate the complement pathway. We have shown that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected RBC and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBC. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action. Understanding how antibodies that are naturally acquired during Plasmodium falciparum infection provide immunity to blood-stage malaria could guide vaccine development. We determined the phenotype and antibody-dependent function of NK cells in a cohort of subjects living in a malaria-endemic region of Mali. Phenotypic markers for 'adaptive' NK cells were also included. Adaptive NK cells were first described in cytomegalovirus (CMV)-infected individuals. CMV-associated human adaptive NK cells can be defined broadly as CD56dim cells that have lost expression of the transcription factor PLZF and lack expression of the signaling proteins FcR gamma chain through epigenetic changes. Multi-parameter flow cytometry revealed a high frequency of adaptive NK cells, which are defined by the absence of both transcription factor PLZF and Fc receptor signaling subunit gamma. These adaptive NK cells dominated the CD16-mediated ADCC response and their relative frequency within the total NK cell population correlated with lower parasitemia and resistance to malaria symptoms. Malaria-susceptible subjects with the largest increase of PLZF-negative NK cells during the malaria transmission season had improved odds of resistance to malaria symptoms during the subsequent season. NK cells from Malian subjects were activated by P. falciparum-infected RBC in vitro after addition of plasma from malaria-resistant individuals. These findings implicate antibody-dependent lysis of P. falciparum-infected RBC by NK cells as a mechanism of acquired immunity to malaria. Consideration of NK cell ADCC responses to potential P. falciparum antigen vaccine targets is therefore warranted in the design and evaluation of malaria vaccines.